Methods for treating gaucher disease

ABSTRACT

Methods for treating Gaucher disease in patients with renal or hepatic impairment.

FIELD OF THE INVENTION

Provided herein are methods for treating Gaucher disease in patientswith renal or hepatic impairment.

BACKGROUND OF THE INVENTION

Glycosphingolipids (GSLs) are a class of naturally-occurring compoundswhich have a multitude of biological functions, including the ability topromote cell growth, cell differentiation, adhesion between cells orbetween cells and matrix proteins, binding of microorganisms and virusesto cells, and metastasis of tumor cells. GSLs are derived fromglucosylceramide (GlcCer), which is produced from ceramide andUDP-glucose by the enzyme UDP-glucose: N-acylsphingosineglucosyltransferase (GlcCer synthase). The structure of ceramide isshown below:

The accumulation of GSL has been linked to a number of diseases,including Tay-Sachs, Gaucher, and Fabry diseases (see, for example, U.S.Pat. No. 6,051,598). Compounds which inhibit glucosylceramide (GlcCer)synthase can lower GSL concentrations and have been reported to beuseful for treating a patient with one of the aforementioned diseases.

Eliglustat is a glucosylceramide synthase inhibitor currently approvedin the United States as a first-line oral therapy for adults withGaucher disease type 1 (GD1), who are CYP2D6 extensive metabolizers(EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs).

Eliglustat (chemical name:N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide)has the structure of Formula (I):

U.S. Pat. No. 7,196,205, for example, describes the preparation andphysical and biological properties of the compound of Formula (I).

Eliglustat is sold in the United States under the brand name Cerdelga®as a hemitartrate salt of formula (Ia):

which is also referred to herein as eliglustat tartrate.

The preparation of eliglustat tartrate is described in, for example,WO2011/066352.

The use of eliglustat or a pharmaceutically acceptable salt thereof fortreating patients who are CYP2D6 extensive metabolizers (EMs),intermediate metabolizers (IMs), or poor metabolizers (PMs) is describedin WO2011/066352.

Eliglustat had not previously been recommended by the FDA and EMA in GD1patients with hepatic impairment or moderate to severe renal impairmentdue to lack of data to make dosage recommendations. It has now beensurprisingly found that eliglustat can be safely used to treat GD1 incertain patients with hepatic or renal impairment.

SUMMARY OF THE INVENTION

Accordingly, provided herein is a method of treating Gaucher diseasecomprising administering to a patient in need thereof an effectiveamount of eliglustat, or a pharmaceutically acceptable salt thereof,wherein said patient is an extensive CYP2D6 metabolizer with mildhepatic impairment (Child-Pugh class A cirrhosis). In one aspect, theeffective amount is a twice daily dose of 84 mg of eliglustat, or apharmaceutically acceptable salt thereof, measured in base form. In oneaspect, the Gaucher disease is Gaucher disease type 1.

In another embodiment, provided herein is a method of treating Gaucherdisease comprising administering to a patient in need thereof anadjusted effective amount of eliglustat, or a pharmaceuticallyacceptable salt thereof, wherein said patient is an extensive CYP2D6metabolizer with mild hepatic impairment and wherein said patient isconcurrently taking a drug that is a weak CYP2D6 inhibitor. In oneaspect of this embodiment, the adjusted effective amount is a once dailydose of 84 mg of eliglustat or a pharmaceutically acceptable saltthereof, measured in base form. In one aspect, the Gaucher disease isGaucher disease type 1.

In another embodiment, provided herein is a method of treating Gaucherdisease comprising administering to a patient in need thereof anadjusted effective amount of eliglustat, or a pharmaceuticallyacceptable salt thereof, wherein said patient is an extensive CYP2D6metabolizer with mild hepatic impairment and wherein said patient isconcurrently taking a drug that is strong, moderate, or weak CYP3Ainhibitor. In one aspect of this embodiment, the adjusted effectiveamount is a once daily dose of 84 mg of eliglustat or a pharmaceuticallyacceptable salt thereof, measured in base form. In one aspect, theGaucher disease is Gaucher disease type 1.

In another embodiment, provided herein is a method of treating Gaucherdisease comprising administering to a patient in need thereof aneffective amount of eliglustat, or a pharmaceutically acceptable saltthereof, wherein said patient is an extensive CYP2D6 metabolizer withmild, moderate, or severe renal impairment. In one aspect of thisembodiment, the effective amount is a twice daily dose of 84 mg ofeliglustat or a pharmaceutically acceptable salt thereof, measured inbase form. In one aspect, the Gaucher disease is Gaucher disease type 1.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows individual C_(max) values after a single dose of 84 mgeliglustat according to the study performed in Example 1.

FIG. 2 shows individual AUC values after a single dose of 84 mgeliglustat according to the study performed in Example 1.

FIG. 3 shows eliglustat concentration-time profiles (mean±SD) byimpairment group following a single 84 mg dose of eliglustat accordingto the study performed in Example 1 (linear-linear scale).

FIG. 4 shows eliglustat concentration-time profiles (mean±SD) byimpairment group following a single 84 mg dose of eliglustat accordingto the study performed in Example 1 (log-linear scale).

FIG. 5 shows individual C_(max) values after a single dose of 84 mgeliglustat according to the study performed in Example 3.

FIG. 6 shows individual AUC values after a single dose of 84 mgeliglustat according to the study performed in Example 3.

DETAILED DESCRIPTION OF THE INVENTION

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

As used herein, “coadministered,” “coadministering,” “in combination,”and “concurrently taking” means being administered or administering atthe same time, in the same day or within a period of 24 hours,particularly within a period of 12 hours.

As used herein, “effective amount” means an amount of eliglustat thatwould be recommended for a patient to take or a doctor would prescribethe patient to take if the patient does not have hepatic impairment orrenal impairment. In one aspect, the effective amount of eliglustat isthe amount approved by U.S. Food and Drug Administration, which is 84 mgtwice daily to patients who are CYP2D6 EMs or IMs, and which is 84 mgonce daily to patients who are PMs. The dose of eliglustat is calculatedbased on its free base form. It should be understood that eliglustat canbe administered as a pharmaceutically acceptable salt, particularly as ahemitartrate, and the amount of salt administered should be adjustedaccordingly.

As used herein, “patient” means a human.

“Pharmaceutically acceptable salt” as used herein means that the saltsof the compound of the present invention can be used in medicinalpreparations.

As used herein, the wording “a compound for use . . . ”, for example,shall be understood as being equivalent to the wording “use of acompound for . . . ” or “use of a compound for the preparation of amedicament for use in . . . ”.

In certain embodiments, a patient's liver function is assessed by theChild-Pugh classification system, which defines three classes of livercirrhosis. In this classification system, points are assigned tomeasurements in one of five categories: levels of total bilirubin, serumalbumin levels, prothrombin time, ascites, and hepatic encephalopathy.Each measure is given a ranking of 1, 2, or 3, and the sum of the fiverankings is the Child-Pugh Score. The Child-Pugh Score is used toclassify hepatic impairment by placing patients in a Child-Pugh class:Child-Pugh class A (mild hepatic impairment), Child-Pugh class B(moderate hepatic impairment), and Child-Pugh class C (severe hepaticimpairment).

In certain embodiments, a patient's renal function is determined bycreatinine clearance calculated by the Cockcroft-Gault formula, whereina subject or patient with a creatinine clearance of >80 mL/min hasnormal renal function, and wherein a subject or patient with acreatinine clearance of 50-80 mL/min has mild renal impairment, andwherein a subject or patient with a creatinine clearance of 30-50 mL/minhas moderate renal impairment, and wherein a subject or patient with acreatinine clearance of <30 mL/min has severe renal impairment.

Eliglustat is metabolized by the liver, primarily by cytochrome P450enzymes. Cytochrome P450s (“CYPs”) are the principal hepatic xenobioticmetabolizing enzymes. There are eleven xenobiotic-metabolizingcytochrome P450s expressed in a typical human liver (i.e., CYP1A2,CYP2A6, CYP2B6, CYP2C8/9/18/19, CYP2D6, CYP2E1 and CYP3A4/5). MainlyCYP2D6 and to a lesser extent CYP3A4 are the primary cytochrome P450isoforms that are responsible for metabolizing eliglustat and itspharmaceutically active salts, such as eliglustat tartrate. The level ofactivity of some P450 enzymes such as CYP2D6 differs according to theindividual CYP2D6 phenotype. For example, individuals can be classifiedas poor, intermediate, extensive, and ultra rapid CYP2D6 metabolizers.

A patient is typically assessed as being a poor, intermediate,extensive, or ultra rapid CYP2D6 metabolizer through genotyping,although rarely the genotype cannot be determined (indeterminatemetabolizer).

For example, a patient can be a poor P450 metabolizer as a result of lowexpression of a P450 enzyme. In such instances, the low expression canbe assessed by determining P450 enzyme expression in the patient, i.e.,genotyping the patient for the P450 enzyme. For example, expression ofCYP2D6 is commonly assessed by PCR (McElroy et. al. “CYP2D6 Genotypingas an Alternative to Phenotyping for Determination of Metabolic Statusin a Clinical Trial Setting”, AAPS Pharmsi (2000) 2(4) article 33) or bymicroarray based pharmacogenomic testing. As such, the patient can beconveniently genotyped for P450 expression (e.g., CYP2D6) prior to theinitiation of treatment and administered an adjusted effective amount,if necessary.

For the CYP2D6 gene, there are four predicted phenotypes:

-   -   As used herein, a “poor CYP2D6 metabolizer” carries two mutant        alleles, which result in complete loss of enzyme activity.    -   As used herein, an “intermediate CYP2D6 metabolizer” possesses        one reduced activity allele and one null allele.    -   As used herein, an “extensive CYP2D6 metabolizer” possesses at        least one and no more than two normal functional alleles.    -   As used herein, an “ultra rapid CYP2D6 metabolizer” carries        multiple copies (3-13) of functional alleles and produce excess        enzymatic activity.

Because eliglustat is metabolized mainly by CYP2D6 and to a lesserextent by CYP3A, eliglustat concentration may be increased in patientswhen co-administered with certain drugs that are CYP2D6 enzymeinhibitors. Examples of weak CYP2D6 inhibitors include, but are notlimited to, escitalopram, abiraterone, diphenhydramine, am iodarone,deramciclane, desvenlafaxine, fosdevirine,daclatasvir/asunaprevir/beclabuvir, oral contraceptives, osilodrostat,propafenone, ritonavir, cimetidine, clobazam, cobicistat, lorcaserin,celecoxib, felodipine, fluvoxamine, gefitinib, hydroxychloroquine,sertraline, vemurafenib, echinacea, escitalopram, hydralazine,panobinostat, ranitidine, verapamil, alogliptin, diltiazem, dulaglutide,lopinavir/ritonavir, sarpogrelate, artesunate/pyronaridine, imatinib,and febuxostat. Examples of moderate CYP2D6 inhibitors include, but arenot limited to, duloxetine, terbinafine, moclobemide, mirabegron,cinacalcet, dronedarone, rolapitant, cimetidine, andtipranavir/ritonavir. Examples of strong CYP2D6 inhibitors include, butare not limited to, paroxetine, fluoxetine, quinidine, bupropion, anddacomitinib.

Patients who are poor CYP2D6 metabolizers have little or no CYP2D6function, so eliglustat metabolism would primarily be via the CYP3Apathway in these patients.

Eliglustat metabolism in these patients may be further impaired as aresult of being treated with certain drugs that are CYP3A enzymeinhibitors. For example, examples of weak CYP3A inhibitors include, butare not limited to, amlodipine, cilostazol, fluvoxamine, goldenseal,isoniazid, ranitidine, and ranolazine. Examples of moderate CYP3Ainhibitors include, but are not limited to, erythromycin, ciprofloxacin,fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir,fosamprenavir, imatinib, cimetidine, amprenavir, casopitant, crizotinib,faldaprevir, ledipasvir, netupitant, nilotinib, tofisopam, dronedarone,cimetidine, and cyclosporine. Examples of strong CYP3A inhibitorsinclude, but are not limited to, ketoconazole, clarithromycin,itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir,telaprevir, tipranavir, posaconazole, voriconazole, telithromycin,conivaptan, boceprevir, idelalisib, mibefradil, nefazodone, nelfinavir,elvitegravir/ritonavir, danopravir/ritonavir, and troleandomycin.

Another embodiment provided herein is a method of providing eliglustat,or a pharmaceutically acceptable salt thereof, wherein the eliglustat,or pharmaceutically acceptable salt thereof, is provided along withinformation indicating that it is useful for treating patients withGaucher disease, particularly adult patients with Gaucher disease type1, and in cases wherein said patient is an extensive CYP2D6 metabolizerwith mild hepatic impairment, no dose adjustment is required. In oneaspect of this embodiment, the recommended or effective amount is 84 mgof eliglustat, measured as a base, twice daily.

Another embodiment provided herein is a method of providing eliglustat,or a pharmaceutically acceptable salt thereof, wherein the eliglustat,or pharmaceutically acceptable salt thereof, is provided along withinformation indicating that it is useful for treating patients withGaucher disease, particularly adult patients with Gaucher disease type1, and in cases wherein said patient is an extensive CYP2D6 metabolizerwith mild hepatic impairment and wherein a weak CYP2D6 inhibitor or astrong, moderate or weak CYP3A inhibitor is coadministered, theeffective amount should be reduced to an adjusted effective amount. Inone aspect of this embodiment, the adjusted effective amount is 84 mg ofeliglustat, measured as a base, once daily.

Another embodiment provided herein is a method of providing eliglustat,or a pharmaceutically acceptable salt thereof, wherein the eliglustat,or pharmaceutically acceptable salt thereof, is provided along withinformation indicating that eliglustat, or pharmaceutically acceptablesalt thereof, is contraindicated in CYP2D6 IMs or PMs with any degree ofhepatic impairment and in CYP2D6 EMs with moderate or severe hepaticimpairment.

Another embodiment provided herein is a method of providing eliglustat,or a pharmaceutically acceptable salt thereof, wherein the eliglustat,or pharmaceutically acceptable salt thereof, is provided along withinformation indicating that it is useful for treating patients withGaucher disease, particularly adult patients with Gaucher disease type1, and in cases wherein said patient is an extensive CYP2D6 metabolizerwith mild, moderate, or severe renal impairment, no dose adjustment isrequired. In one aspect of this embodiment, the recommended or effectiveamount is 84 mg of eliglustat, measured as a base, twice daily.

Another embodiment provided herein is a method of providing eliglustat,or a pharmaceutically acceptable salt thereof, wherein the eliglustat,or pharmaceutically acceptable salt thereof, is provided along withinformation indicating that eliglustat, or pharmaceutically acceptablesalt thereof, is not recommended or should be avoided in CYP2D6 EMs withend-stage renal disease and CYP2D6 IMs or PMs with mild, moderate, orsevere renal impairment or end-stage renal disease.

Another embodiment provided herein is an article of manufacturecomprising

-   -   a) a packaging material;    -   b) eliglustat, or a pharmaceutically acceptable salt thereof;        and    -   c) a label or package insert contained within the packaging        material indicating that eliglustat, or a pharmaceutically        acceptable salt thereof, is contraindicated in CYP2D6        intermediate metabolizers (IMs) or poor metabolizers (PMs) with        any degree of hepatic impairment and in CYP2D6 extensive        metabolizers (EMs) with moderate or severe hepatic impairment.

Another embodiment provided herein is an article of manufacturecomprising

-   -   a) a packaging material;    -   b) eliglustat, or a pharmaceutically acceptable salt thereof;        and    -   c) a label or package insert contained within the packaging        material indicating that no dose adjustment of eliglustat, or a        pharmaceutically acceptable salt thereof, is required in CYP2D6        extensive metabolizers (EMs) with mild hepatic impairment.

Another embodiment provided herein is an article of manufacturecomprising

-   -   a) a packaging material;    -   b) eliglustat, or a pharmaceutically acceptable salt thereof;        and    -   c) a label or package insert contained within the packaging        material indicating that eliglustat, or a pharmaceutically        acceptable salt thereof, is contraindicated in extensive        metabolizers (EMs) with mild hepatic impairment taking a strong        or moderate CYP2D6 inhibitor; and in CYP2D6 extensive        metabolizers (EMs) with mild hepatic impairment taking a weak        CYP2D6 inhibitor or a strong, moderate or weak CYP3A inhibitor,        a dose of 84 mg eliglustat once daily should be considered.

Another embodiment provided herein is an article of manufacturecomprising

-   -   a) a packaging material;    -   b) eliglustat, or a pharmaceutically acceptable salt thereof;        and    -   c) a label or package insert contained within the packaging        material indicating that no dose adjustment of eliglustat, or a        pharmaceutically acceptable salt thereof, is required in CYP2D6        extensive metabolizers with mild, moderate, or severe renal        impairment.

Another embodiment provided herein is an article of manufacturecomprising

-   -   a) a packaging material;    -   b) eliglustat, or a pharmaceutically acceptable salt thereof;        and    -   c) a label or package insert contained within the packaging        material indicating that eliglustat, or a pharmaceutically        acceptable salt thereof, is not recommended or should be avoided        in CYP2D6 extensive metabolizers (EMs) with end-stage renal        disease.

Another embodiment provided herein is an article of manufacturecomprising

-   -   a) a packaging material;    -   b) eliglustat, or a pharmaceutically acceptable salt thereof;        and    -   c) a label or package insert contained within the packaging        material indicating that eliglustat, or a pharmaceutically        acceptable salt thereof, is should be avoided in intermediate        metabolizers (IMs) or poor metabolizers (PMs) with mild,        moderate or severe renal impairment or end-stage renal disease.

Another embodiment provided herein is a package comprising eliglustat,or a pharmaceutically acceptable salt thereof, and a label, said labelcomprising a printed statement which informs a prospective user thateliglustat, or pharmaceutically acceptable salt thereof, is i) indicatedfor the treatment of Gaucher disease type 1 and ii) is contraindicatedin CYP2D6 intermediate metabolizers (IMs) or poor metabolizers (PMs)with any degree of hepatic impairment and in CYP2D6 extensivemetabolizers (EMs) with moderate or severe hepatic impairment.

Another embodiment provided herein is a package comprising eliglustat,or a pharmaceutically acceptable salt thereof, and a label, said labelcomprising a printed statement which informs a prospective user thateliglustat, or pharmaceutically acceptable salt thereof, is i) indicatedfor the treatment of Gaucher disease type 1 and ii) contraindicated inextensive metabolizers (EMs) with mild hepatic impairment taking astrong or moderate CYP2D6 inhibitor. In CYP2D6 extensive metabolizers(EMs) with mild hepatic impairment taking a weak CYP2D6 inhibitor or astrong, moderate or weak CYP3A inhibitor, a dose of 84 mg eliglustatonce daily should be considered.

Another embodiment provided herein is a package comprising eliglustat,or a pharmaceutically acceptable salt thereof, and a label, said labelcomprising a printed statement which informs a prospective user thateliglustat, or pharmaceutically acceptable salt thereof, is i) indicatedfor the treatment of Gaucher disease type 1 and ii) not recommended orshould be avoided in CYP2D6 extensive metabolizers (EMs) with end-stagerenal disease (ESRD).

Another embodiment provided herein is a package comprising eliglustat,or a pharmaceutically acceptable salt thereof, and a label, said labelcomprising a printed statement which informs a prospective user thateliglustat, or pharmaceutically acceptable salt thereof, is i) indicatedfor the treatment of Gaucher disease type 1 and ii) not recommended inintermediate metabolizers (IMs) or poor metabolizers (PMs) with mild,moderate or severe renal impairment or end-stage renal disease, andeliglustat is not recommended or should be avoided in CYP2D6 extensivemetabolizers (EMs) with end-stage renal disease.

Another embodiment provided herein is a method for treating Gaucherdisease, comprising administering an adjusted effective amount ofeliglustat, or a pharmaceutically acceptable salt thereof, to a patientin need thereof in combination with a weak CYP2D6 inhibitor, whereinsaid patient is a CYP2D6 extensive metabolizer and wherein said patienthas mild hepatic impairment. In one aspect of this embodiment, theadjusted effect amount of eliglustat, or pharmaceutically acceptablesalt thereof, is a dose of 84 mg of eliglustat, measured in base form,once daily. In another aspect, the weak CYP2D6 inhibitor isescitalopram, abiraterone, diphenhydramine, amiodarone, deramciclane,desvenlafaxine, fosdevirine, daclatasvir/asunaprevir/beclabuvir, oralcontraceptives, osilodrostat, propafenone, ritonavir, cimetidine,clobazam, cobicistat, lorcaserin, celecoxib, felodipine, fluvoxamine,gefitinib, hydroxychloroquine, sertraline, vemurafenib, echinacea,escitalopram, hydralazine, panobinostat, ranitidine, verapamil,alogliptin, diltiazem, dulaglutide, lopinavir/ritonavir, sarpogrelate,artesunate/pyronaridine, imatinib, or febuxostat. In another aspect, theGaucher disease is Gaucher disease type 1.

Another embodiment provided herein is a method for treating Gaucherdisease, comprising administering an adjusted effective dose ofeliglustat, or a pharmaceutically acceptable salt thereof, to a patientin need thereof in combination with a strong, moderate or weak CYP3Ainhibitor, wherein said patient is a CYP2D6 extensive metabolizer andwherein said patient has mild hepatic impairment. In one aspect of thisembodiment, the adjusted effect amount of eliglustat, orpharmaceutically acceptable salt thereof, is a dose of 84 mg ofeliglustat, measured in base form, once daily. Examples of weak CYP3Ainhibitors include amlodipine, cilostazol, fluvoxamine, goldenseal,isoniazid, ranitidine, and ranolazine. In one aspect, the moderate CYP3Ainhibitor is selected from the group consisting of erythromycin,ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant,atazanavir, darunavir, fosamprenavir, imatinib, cimetidine, amprenavir,casopitant, crizotinib, faldaprevir, ledipasvir, netupitant, nilotinib,tofisopam, dronedarone, cimetidine, and cyclosporine. In one aspect thestrong CYP3A inhibitor is selected from the group consisting ofketoconazole, clarithromycin, itraconazole, cobicistat, indinavir,lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole,voriconazole, telithromycin, conivaptan, boceprevir, idelalisib,mibefradil, nefazodone, nelfinavir, elvitegravir/ritonavir,danopravir/ritonavir, and troleandomycin. In another aspect, the Gaucherdisease is Gaucher disease type 1.

In another embodiment, provided herein is eliglustat or apharmaceutically acceptable salt thereof for use in treating Gaucherdisease in a patient, wherein the patient is an extensive CYP2D6metabolizer with mild hepatic impairment. In one aspect, eliglustat, ora pharmaceutically acceptable salt thereof, is administered in aneffective amount wherein the effective amount is a twice daily dose of84 mg, measured in base form. In another aspect, the Gaucher disease isGaucher disease type 1.

In another embodiment, provided herein is eliglustat, or apharmaceutically acceptable salt thereof, for use in treating Gaucherdisease in patient, wherein the patient is an extensive CYP2D6metabolizer with mild hepatic impairment and wherein said patient isconcurrently taking a drug that is a weak CYP2D6 inhibitor. In oneaspect, the eliglustat, or a pharmaceutically acceptable salt thereof,is administered in an adjusted effective amount, wherein the adjustedeffective amount is a once daily dose of 84 mg of eliglustat, or apharmaceutically acceptable salt thereof, measured in base form. Inanother aspect, the weak CYP2D6 inhibitor is selected from escitalopram,abiraterone, diphenhydramine, amiodarone, deramciclane, desvenlafaxine,fosdevirin, daclatasvir/asunaprevir/beclabuvir, oral contraceptives,osilodrostat, propafenone, ritonavir, cimetidine, clobazam, cobicistat,lorcaserin, celecoxib, felodipine, fluvoxamine, gefitinib,hydroxychloroquine, sertraline, vemurafenib, echinacea, escitalopram,hydralazine, panobinostat, ranitidine, verapamil, alogliptin, diltiazem,dulaglutide, lopinavir/ritonavir, sarpogrelate, artesunate/pyronaridine,imatinib, and febuxostat. In another aspect, the Gaucher disease isGaucher disease type 1.

In another embodiment, provided herein is eliglustat, or apharmaceutically acceptable salt thereof, for use in treating Gaucherdisease in a patient, wherein the patient is an extensive CYP2D6metabolizer with mild hepatic impairment and wherein said patient isconcurrently taking a drug that is strong, moderate, or weak CYP3Ainhibitor. In one aspect of this embodiment, the eliglustat, or apharmaceutically acceptable salt thereof, is administered in an adjustedeffective amount, wherein the adjusted effective amount is a once dailydose of 84 mg of eliglustat or a pharmaceutically acceptable saltthereof, measured in base form. In one aspect, the weak CYP3A inhibitoris, for example, selected from amlodipine, cilostazol, fluvoxamine,goldenseal, isoniazid, ranitidine, and ranolazine. In one aspect, themoderate CYP3A inhibitor is, for example, selected from the groupconsisting of erythromycin, ciprofloxacin, fluconazole, diltiazem,verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib,and cimetidine. In one aspect the strong CYP3A inhibitor is, forexample, selected from the group consisting of ketoconazole,clarithromycin, itraconazole, cobicistat, indinavir, lopinavir,ritonavir, saquinavir, telaprevir, tipranavir, posaconazole,voriconazole, telithromycin, conivaptan, and boceprevir. In anotheraspect, the Gaucher disease is Gaucher disease type 1.

In another embodiment, provided herein is eliglustat or apharmaceutically acceptable salt thereof for use in treating Gaucherdisease in a patient, wherein the patient is an extensive CYP2D6metabolizer with mild, moderate, or severe renal impairment. In oneaspect of this embodiment, the eliglustat, or a pharmaceuticallyacceptable salt thereof, is administered in an effective amount, whereinthe effective amount is a twice daily dose of 84 mg of eliglustat or apharmaceutically acceptable salt thereof, measured in base form. Inanother aspect, the Gaucher disease is Gaucher disease type 1.

For their therapeutic use, eliglustat and pharmaceutically acceptablesalts thereof are generally introduced into pharmaceutical compositions.

These pharmaceutical compositions comprise eliglustat or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients.

Said excipients are chosen according to the pharmaceutical form and themethod of administration desired, from the usual excipients which areknown to those skilled in the art.

By way of example, a dose of eliglustat or a pharmaceutically acceptablesalt thereof, in capsule form, may correspond to the following example:A capsule for oral use comprising 84 mg of eliglustat (equivalent to 100mg of the hemitartrate salt), microcrystalline cellulose, lactosemonohydrate, hypromellose and glyceryl behenate.

The present invention may be better understood by reference to thefollowing non-limiting examples, which is exemplary of the invention. Itshould in no way be construed, however, as limiting the breath of thescope of the invention.

Example 1

A multi-center, open-label, single oral dose study of eliglustattartrate administered to mild or moderate HI and normal hepatic function(healthy) matched (by body weight and cytochrome P450 [CYP] 2D6phenotype) subjects was carried out to study the effect of mild andmoderate hepatic impairment (HI) on the pharmacokinetics (PK) ofeliglustat.

Approximately 8 subjects were planned to be enrolled into each HI group(mild or moderate HI) and 8 subjects with normal hepatic functionmatched to impaired subjects by weight and CYP2D6 phenotype. At least 6CYP2D6 extensive metabolizers (EMs) were to be enrolled into eachimpairment group, with the remaining 2 subjects enrolled according tothe following preference: at least 20 subjects were to be screened foreach impairment group and if identified, up to 2 CYP2D6 poormetabolizers (PMs) were enrolled. If less than 2 PMs were identified, upto 2 CYP2D6 intermediate metabolizers (IMs) were to be enrolled for atotal of 8 subjects per group. If less than 2 PMs or IMs wereidentified, up to 2 additional EMs were to be enrolled for a total of 8subjects per group. If 2 PMs were identified prior to screening 20subjects, screening may have been discontinued. If an eligible PMsubject was identified after satisfying the above requirements andenrolling 8 subjects for an impairment group, this subject may stillhave been enrolled for that impairment group.

CYP2D6 EMs and IMs were to receive a single 100-mg dose of eliglustattartrate, while CYP2D6 PMs were to receive a single 50-mg dose ofeliglustat tartrate.

Diagnosis and Criteria for Inclusion:

For HI subjects: Male (body weight between 50.0 and 125.0 kg, inclusive)or female subjects (body weight between 40.0 and 110.0 kg, inclusive)between 18 and 79 years, inclusive, with a body mass index between 18.0and 37 kg/m², inclusive; having stable chronic liver disease assessed bymedical history, physical examination, and laboratory values; withmoderate HI (defined as Child-Pugh score of 7 to 9, inclusive) or mildHI (defined as Child-Pugh score of 5 to 6, inclusive). For healthysubjects: Male or female subjects, between 18 and 79 years, inclusive;body weight within 15% of the body weight of matched subjects with HI,and body mass index between 18.0 and 37 kg/m², inclusive; healthysubjects were also matched to HI groups by CYP2D6 phenotype predictedfrom genotype.

Dose Regimen:

A single 100-mg capsule of eliglustat tartrate (equivalent to 84 mg ofeliglustat) was administered to CYP2D6 EM or IM subjects with mild ormoderate HI and matching healthy subjects.

A single 50-mg capsule of eliglustat tartrate (equivalent to 42 mg ofeliglustat) was to be administered to CYP2D6 PM with mild or moderate HIand matching healthy subjects.

Criteria for Evaluation:

Pharmacokinetics: The following PK parameters were calculated foreliglustat plasma concentrations using noncompartmental methods: Maximumplasma concentration observed (C_(max)), area under the plasmaconcentration versus time curve calculated using the trapezoidal methodfrom time zero to the time corresponding to the last quantifiableconcentration t_(last) (AUC_(last)), time to reach C_(max) (t_(max)),area under the plasma concentration versus time curve extrapolated toinfinity (AUC), terminal half-life associated with the terminal slope λz(t_(1/2z)), time corresponding to the last concentration above the limitof quantification (t_(last)), apparent total body clearance of a drugfrom the plasma (CL/F), and apparent volume of distribution during theterminal (λz) phase (Vz/F).

Pharmacokinetic Sampling Times and Bioanalytical Methods:

Blood samples were collected at the following timepoints to assessplasma concentrations of eliglustat: predose and 0.5, 1, 1.5, 2, 2.5, 3,4, 6, 8, 10, 12, 24, 36, and 48 hours postdose.

Eliglustat concentrations in plasma were determined using a validatedliquid chromatography-tandem mass spectrometry method with a lower limitof quantification of 0.2 ng/mL.

Statistical Methods:

Pharmacokinetics

Eliglustat PK parameters were summarized using descriptive statisticsfor each population group and for each CYP2D6 phenotype. Forlog-transformed C_(max), AUC_(last), AUC, t_(1/2z), CL/F and Vz/F, theeffect of hepatic impairment on a single dose of eliglustat tartrate oneliglustat PK parameters were analyzed using a linear fixed effectsmodel for CYP2D6 EM subjects. Estimate and 90% confidence interval (CI)for geometric mean of each population group and also for the geometricmean ratio of each hepatic impaired group versus the normal controlgroup were provided for each parameter.

Safety

The safety evaluation was based upon the review of the individual values(clinically significant abnormalities) and descriptive statistics(summary tables). All safety analyses were performed using the safetypopulation and were based on the on-treatment phase (defined as the timefrom investigational medicinal product [IMP] administration up to Day 3visit, inclusive). For laboratory, vital signs, and ECG data,potentially clinically significant abnormalities (PCSAs) were analyzedusing the 24 May 2014 version of the PCSA list. Electrocardiogramparameters were obtained from automatic reading of 12-lead ECGs and wereanalyzed as raw parameter values and change from baseline. For vitalsigns, raw data and changes from baseline were summarized usingdescriptive statistics by population group and time point. Allindividual data for biochemistry, hematology, and qualitative urinarytests were listed.

Adverse events were coded according to the Medical Dictionary forRegulatory Activities (MedDRA v.19.1) and classified into predefinedstandard categories according to chronological criteria:

-   -   Pretreatment adverse events (AEs), defined as AEs that occurred,        worsened (according to Investigator opinion), or became serious        during the pretreatment phase (defined as the time between the        signature of the informed consent and IMP administration        [excluded]);    -   Treatment-emergent AEs (TEAEs), defined as AEs that occurred,        worsened, or became serious during the on-treatment phase;    -   Posttreatment AEs, defined as AEs that occurred, worsened, or        became serious during the posttreatment phase (defined as the        time after Day 3 visit through completion of EOS).

All AEs reported in the study were listed and sorted by subject, onsetdate and time. The number and percentage of subjects with TEAEs werelisted by population group, primary system-organ class (SOC), preferredterm (PT), and AE diagnosis.

Population Characteristics:

Eight subjects were enrolled into each group. Seven CYP2D6 EMs and 1CYP2D6 IM, each, were enrolled into the moderate impairment group andthe healthy matched group, and 6 CYP2D6 EMs and 2 CYP2D6 IMs wereenrolled into the mild impairment group.

Pharmacokinetic Results:

Mean±SD (Geometric Mean) [CV %] PK parameters of eliglustat in CYP2D6 EMsubjects after a single dose of 100 mg eliglustat tartrate

Plasma Eliglustat CYP2D6 EM Subjects CYP2D6 IM Subjects ParameterHealthy Mild HI Moderate HI Healthy Mild HI Moderate HI N 7   6   7   1 2 1 C_(max) 10.4 ± 7.40 22.4 ± 30.2 39.5 ± 43.4 75.9   35.9 35.6(ng/mL) (8.81) (10.7) (24.8) (26.7, 45.1) [70.9] [135.1] [110.0] t_(max)^(a) 2.50 1.75 4.00 2.50    2.00 1.52 (h) (1.00-3.00) (1.00-6.00)(1.00-6.00) (2.00, 2.00) AUC_(last) 63.9 ± 47.1 166 ± 285 536 ± 642 568334 197 (ng · h/mL) (54.7) (64.3) (293) (187, 481) [73.7] [171.3][119.6] AUC 69.0 ± 49.1 172 ± 293 575 ± 696 578 346 208 (ng · h/mL)(59.5) (68.5) (307) (190, 501) [71.2] [170.5] [121.0] t_(1/2z)  7.08 ±0.881 7.25 ± 1.46 10.5 ± 2.25 8.48    9.34 5.87 (h) (7.03) (7.13) (10.3)(8.27, 10.4) [12.5] [20.1] [21.4] CL/F 1570 ± 628  1980 ± 1440 416 ± 295146 306 406 (L/h) (1420) (1230) (275) (168, 444) [40.1] [72.8] [70.9]Vz/F 16030 ± 6020  20000 ±15600  5840 ± 4130 1790 3910  3430 (L) (14400)(12700) (4090) (2520, 5300) [37.5] [78.2] [70.7] t_(last) ^(a) 24.00 30.00  48.00  48.00    48.00 24.00 (h) (24.00-24.05) (24.00-48.00)(36.00-48.00) (48.00, 48.00) ^(a)Median (Min-Max) b Mean (Min, Max) forN = 2

Point estimates of geometric mean ratio with 90% CI in CYP2D6 EMsubjects Parameter Comparison Estimate 90% CI C_(max) Mild HI vs Healthy1.22 (0.46 to 3.23) Moderate HI vs Healthy 2.81 (1.10 to 7.17)AUC_(last) Mild HI vs Healthy 1.18 (0.42 to 3.28) Moderate HI vs Healthy5.35 (2.00 to 14.35) AUC Mild HI vs Healthy 1.15 (0.41 to 3.19) ModerateHI vs Healthy 5.16 (1.93 to 13.74) t_(1/2z) Mild HI vs Healthy 1.01(0.85 to 1.21) Moderate HI vs Healthy 1.47 (1.24 to 1.74) CL/F Mild HIvs Healthy 0.87 (0.31 to 2.41) Moderate HI vs Healthy 0.19 (0.07 to0.52) Vz/F Mild HI vs Healthy 0.88 (0.34 to 2.29) Moderate HI vs Healthy0.28 (0.11 to 0.71)

Compared to healthy CYP2D6 EMs, eliglustat mean C_(max) and AUC wasslightly higher in CYP2D6 EMs with mild HI (1.22 and 1.15 fold,respectively) and appreciably higher in subjects with moderate HI (2.81and 5.16 fold, respectively) following a single 100-mg dose ofeliglustat tartrate. Mean t_(1/2z) values were similar in mild HIsubjects and healthy subjects, but were prolonged in moderate HIsubjects (10.5 hours versus 7.08 hours).

Safety Results:

A total of 6 mild TEAEs were observed in 5 subjects. Four TEAEs in 3subjects were considered related to study drug by the investigator:dysgeusia in 2 subjects with moderate HI and nausea and headache in 1healthy subject. No serious adverse events were reported, and there wereno deaths or other significant AEs. There were no treatment emergentPCSA that were clinically relevant for the laboratory values or forvital signs and ECGs.

Example 2

A physiologically-based pharmacokinetic (PBPK) model developed usingeliglustat preclinical and clinical study results was verified using theobserved single-dose data in both healthy and hepatic impaired patientsfrom the study described in Example 1. This PBPK model was used topredict eliglustat exposures after repeated dosing of eliglustat inCYP2D6 EM subjects with mild and moderate HI as well as in CYP2D6 EMhealthy subjects (without HI) for comparison. Simulation of eliglustatPK was conducted with 10 virtual trials of 10 subjects/category afterrepeated dosing of 84 mg twice daily (BID) or once daily (QD) eliglustatoral dose alone for 8 days, and the simulation results are presented inTable 1.

TABLE 1 Simulated Mean (Range of the 10 Means of the 10 Trials)Steady-State Exposure after Oral Administration of Eliglustat in CYP2D6EMs (Healthy, Mild HI and Moderate HI) 84 mg BID^(a) Ratio^(b) 84 mgQD^(a) C_(max) AUC_(0-tau) (HI/Healthy) C_(max) AUC_(0-tau) CYP2D6 EM(ng/mL) (ng · h/mL) C_(max) AUC_(0-tau) (ng/mL) (ng · h/mL) Healthy 27199 — — 17.9 146 (17.0, 37.2) (114, 291) (12.7, 22.2) (94.5, 203)  MildHI 64.2 568 2.38 2.85 32.9 351 (39.1, 97.0) (322, 893) (22.2, 49.5)(215, 606) Moderate HI 173 1760  6.41 8.86 83.5 1270  (127, 235) (1270,2470) (59.2, 115)   (852, 1890) AUC_(0-tau) = area under the plasmaconcentration versus time curve from time zero to the end of the dosinginterval of 12 hours for BID and 24 hours for QD (AUCo-tau representsAUC₀₋₁₂ for BID regimen and AUC₀₋₂₄ for QD regimen); BID = twice daily;C_(max) = maximum observed plasma concentration; EM = extensivemetabolizer; QD = once daily; HI = hepatic impairment ^(a)Values arereported to 3 significant figures ^(b)Ratio of the mean exposures

To ensure that eliglustat exposure will remain within the range ofeliglustat exposures that has been demonstrated to be safe andefficacious in the clinical development program, 84 mg QD of eliglustatwhen coadministered with CYP2D6 inhibitors or CYP3A inhibitors wasevaluated using PBMK modeling for CYP2D6 EM subjects with mild HI.Various scenarios of coadministration of eliglustat 84 mg QD with CYP2D6inhibitors or CYP3A inhibitors were simulated using Simcyp build-inmodel of inhibitors with minor modifications as needed. Paroxetine,terbinafine, and ritonavir were used as strong, moderate, and weakCYP2D6 inhibitors, respectively, while ketoconazole, fluconazole, andfluvoxamine were used as strong, moderate, and weak CYP3A inhibitors,respectively. Simulation of eliglustat PK was conducted with 10 virtualtrials of 10 CYP2D6 EM subjects with mild HI after repeated dosing of 84mg QD eliglustat alone for 8 days (from Day 1 to Day 8) and with CYP2D6or CYP3A inhibitors for an additional 7 or 10 days (Day 9 to Day 15 orDay 9 to Day 18). The PBPK-predicted eliglustat mean (range of the meansof the 10 virtual trials) exposures in CYP2D6 EMs with mild HI uponcoadministration of eliglustat with CYP2D6 or CYP3A inhibitors arepresented in Table 2. Simulated exposures in healthy EMs and EMs withmild HI following eliglustat alone at 84 mg BID were also included forcomparison.

TABLE 2 Simulated Mean (Range of the 10 Means of the 10 Trials)Steady-State Exposure in CYP2D6 EMs (Heathy and Mild HI) after OralAdministration of Eliglustat with and without CYP2D6 or CYP3A InhibitorsEliglustat + CYP CYP Inhibitor Inhibitor CYP Inhibitor C_(max) ^(a)AUC_(0-tau) ^(a) Eliglustat Population Type (dose) (ng/mL) (ng · h/mL)84 mg BID Healthy None — 27 199 (17.0, 37.2) (114, 291) 84 mg BID MildHI None — 64.2 568 (39.1, 97.0) (322, 893) 84 mg QD Mild HI StrongParoxetine 155 2630 CYP2D6 (30 mg QD) (119, 192) (1840, 3450) inhibitor84 mg QD Mild HI Strong Ketoconazole 71.7 1060 CYP3A (400 mg QD) (32.8,138) (377, 2380) inhibitor 84 mg QD Mild HI Moderate Terbinafine 96.91350 CYP2D6 (250 mg QD) (82.1, 110) (1080, 1580) inhibitor 84 mg QD MildHI Moderate Fluconazole 53.5 700 CYP3A (400 mg (31.6, 83.7) (342, 1240)inhibitor loading dose + 200 mg QD) 84 mg QD Mild HI Weak Ritonavir 45.5529 CYP2D6 (100 mg BID) (31.0, 64.9) (361, 797) inhibitor 84 mg QD MildHI Weak Fluvoxamine 42.4 482 CYP3A (300 mg QD) (26.4, 65.9) (281, 850)inhibitor AUC_(0-tau) = area under the plasma concentration versus timecurve from time zero to the end of the dosing interval of 12 hours forBID and 24 hours for QD (AUC_(0-tau) represents AUC₀₋₁₂ for BID regimenand AUC₀₋₂₄ for QD regimen); BID = twice daily; C_(max) = maximumobserved plasma concentration; QD = once daily. ^(a)Values were reportedto 3 significant figures

Example 3

A phase 1, open-label, 2-stage, pharmacokinetic and tolerability studyof single dose eliglustat tartrate in subjects with renal impairment(RI) (mild, moderate, and severe) and subjects with normal renalfunction, matched to RI subjects by age, weight, and cytochrome P450[CYP] 2D6 phenotype was carried out to study the effect of mild,moderate, and severe RI on the pharmacokinetics (PK) of eliglustat.

Methodology: A phase 1, open-label, 2-stage, pharmacokinetic andtolerability study of single dose eliglustat tartrate in subjects withrenal impairment (RI) (mild, moderate, and severe) and subjects withnormal renal function, matched to RI subjects by age, weight, andcytochrome P450 [CYP] 2D6 phenotype.

Approximately 32 subjects were planned to be enrolled in 2 stages: Stage1 comprised of 8 subjects with severe RI and 8 subjects with normalrenal function, matched by CYP2D6 phenotype, weight, and age. Subjectswith mild and moderate RI would have been enrolled in Stage 2 if theresults in subjects with severe RI showed a substantial effect ofreduced renal function on eliglustat PK compared to the matched normalfunction subjects. Stage 2 was to include 8 subjects with mild and 8subjects with moderate RI. Each cohort was to enroll at least 6 CYP2D6extensive metabolizers (EMs). The remaining 2 subjects were to be poormetabolizers (PMs), intermediate metabolizers (IMs) or EMs, enrolledaccording to the following preference: at least 20 subjects were to bescreened for each cohort and if identified, up to 2 PMs were to beenrolled. If less than 2 PMs were identified, up to 2 IMs were to beenrolled for a total of 8 subjects. If less than 2 PMs and IMs wereidentified, up to 2 additional EMs were to be enrolled for a total of 8subjects. Allowed concomitant medications included no more than one weakCYP3A inhibitor and one weak CYP2D6 inhibitor, alone or in combination.

CYP2D6 EMs and IMs were to receive a single 100 mg dose of eliglustattartrate while CYP2D6 PMs were to receive a single 50 mg dose ofeliglustat tartrate.

Diagnosis and Criteria for Inclusion:

For RI subjects: Male (body weight between 50.0 and 125.0 kg, inclusive)and female (body weight between 40.0 and 110.0 kg, inclusive) subjectsbetween 18 and 79 years, with a body mass index (BMI) between 18.0 and37.0 kg/m2, inclusive, having mild, moderate or severe RI determined bya creatinine clearance (CrCl), calculated by Cockcroft-Gault formula, of50-80 mL/min, 30-50 mL/min or <30 mL/min, respectively.

Normal renal function subjects: Male or female subjects, between 18 and79 years, inclusive, body weight within 15% of the body weight ofmatched subject with RI, BMI between 18.0 and 37.0 kg/m² and a CrClof >80 mL/min. Healthy subjects were also matched by age and CYP2D6predicted phenotype based on genotype.

Dose Regimen:

A single 100 mg capsule of eliglustat tartrate (equivalent to 84 mg ofeliglustat) was to be administered to CYP2D6 EM or IM subjects with RIand matching healthy subjects.

A single 50 mg capsule of eliglustat tartrate (equivalent to 42 mg ofeliglustat) was to be administered to CYP2D6 PM subjects with RI andmatching healthy subjects.

Criteria for Evaluation:

Pharmacokinetics: Plasma eliglustat concentrations were used todetermine the following PK parameters using noncompartmental methods:Maximum plasma concentration observed (C_(max)), first time to reachC_(max)(t_(max)), area under the plasma concentration versus time curvecalculated using the trapezoidal method from time zero to the timecorresponding to the last concentration above the limit ofquantification, t_(last) (AUC_(last)), area under the plasmaconcentration time curve extrapolated to infinity (AUC), terminalhalf-life associated with the terminal slope λz (t_(1/2z)), apparenttotal body clearance of a drug from plasma (CL/F), and apparent volumeof distribution during the terminal phase (VZ/F).

Pharmacokinetic/Pharmacodynamics Sampling Times and BioanalyticalMethods:

Blood samples were collected at the following time points to assessplasma concentrations of eliglustat: predose, and 0.5, 1, 1.5, 2, 2.5,3, 4, 6, 8, 10, 12, 24, and 36 hours postdose.

Eliglustat concentrations in plasma were determined using a validatedliquid chromatography tandem mass spectrometry method with a lower limitof quantification (LLOQ) of 0.2 ng/mL.

Statistical Methods:

Pharmacokinetics:

Eliglustat PK parameters were summarized using descriptive statisticsfor each population group and for each CYP2D6 phenotype. Forlog-transformed C_(max), AUC_(last), AUC, t_(1/2z), CL/F, and Vz/F, theeffect of severe RI on eliglustat PK parameters after a single dose ofeliglustat tartrate was analyzed using a linear fixed effects model onCYP2D6 EM subjects. Inclusion of population, CYP3A weak inhibitor, age,and weight as covariate was selected manually, choosing the model withthe lowest AIC value. After testing, the final model chosen were thosewith only population as fixed term. Estimate and 90% confidence interval(CI) for the geometric mean of each population group and for thegeometric mean ratio of severe RI group versus the normal control groupwere provided from this model for each parameter.

Safety:

The safety evaluation was based on the review of the individual values(clinically significant abnormalities) and descriptive statistics(summary tables). All safety analyses were performed using the safetypopulation and based on the on-treatment phase (defined as the starttime of investigational medicinal product [IMP] administration up to Day3 visit). For laboratory, vital sign, and ECG data, the PotentiallyClinically Significant Abnormalities (PCSAs) were analyzed using PCSAlist (Version 3.0, 24 May 2014). Electrocardiogram parameters wereobtained from automatic reading of the 12-lead ECGs and were analyzed asraw parameter value and change from baseline. For vital signs, raw dataand changes from baseline were summarized using descriptive statisticsby population group and time of measurement. All individual data forbiochemistry, hematology, and qualitative urinary tests were listed.

Vital signs and ECG readings were analyzed as raw parameter value andchange from baseline.

Adverse events were coded according to the Medical Dictionary forRegulatory Activities (MedDRA, version 19.1). They were classified intopre-defined standard categories according to chronological criteria:

-   -   Pretreatment adverse events: AEs that occurred, worsened        (according to the Investigator's opinion) or became serious        during the pretreatment phase (defined as the time between the        signature of the informed consent and IMP administration        [excluded]);    -   Treatment-emergent adverse events (TEAEs): AEs that occurred,        worsened or became serious during the on-treatment phase;    -   Posttreatment adverse events: AEs that occurred, worsened or        became serious during the posttreatment phase (defined as        starting after the Day 3 visit and ending with EOS).

The number and percentage of subjects with TEAEs were listed bypopulation group, primary system-organ class (SOC), preferred term (PT),and AE diagnosis.

Population Characteristics:

A total of 16 subjects were enrolled: 8 subjects were enrolled into thesevere RI cohort and 8 into the healthy matched cohort. For each cohort,7 subjects were CYP2D6 EMs and 1 subject was CYP2D6 IM. Since Stage 1did not show a substantial effect of severe RI on eliglustat PK comparedto the matched normal renal function in EMs, Stage 2 of the study wasnot undertaken. Five EMs subjects in the severe RI cohort wereconcomitantly taking a weak CYP3A inhibitor (amlodipine) and 1 IMsubject in the severe renal impairment cohort was taking both a weakCYP2D6 inhibitor (escitalopram) and a weak CYP3A inhibitor (amlodipine).None of the healthy matched subjects were taking CYP2D6 or CYP3Ainhibitors.

Pharmacokinetic results: Mean ± SD (Geometric Mean) [CV %] plasma PKparameters of eliglustat after a single oral dose of 100 mg eliglustattartrate CYP2D6 EM Subjects CYP2D6 IM Subjects Parameter Healthy SevereRI Healthy Severe RI N 7   7   1 1 C_(max) 17.6 ± 13.2 12.7 ± 4.85 54.7220 (ng/mL) (13.4) [75.2] (11.8) [38.1] t_(max) ^(a) 1.50 4.00 3 4 (h)(0.50-6.00) (1.00-6.00) AUC_(last)  112 ± 68.7  102 ± 41.7 520 3590 (ng· h/mL) (96.0) [61.1] (95.5) [40.7] AUC  118 ± 71.1  107 ± 42.1 559NR^(b) (ng · h/mL)  (101) [60.3] (99.8) [39.5] t_(1/2z) 8.50 ± 1.51 6.56 ± 0.876 9.59 NR^(b) (h) (8.39) [17.8] (6.51) [13.3] CL/F 963 ± 532903 ± 354 151 NR^(b) (L/h)  (834) [55.2]  (845) [39.2] Vz/F 11700 ±6710  8480 ± 3190 2090 NR^(b) (L) (10100) [57.5]  (7940) [37.7] t_(last) ^(a) 36.00  36.00  36.00 36.00 (h) (24.00-36.00) (24.00-36.00)^(a)Median (Min-Max) ^(b)NR: not reported. AUC, CL/F, t_(1/2) andV_(z)/F values were not reported due to % AUC extrapolation greater than20% of total AUC

Point estimates of geometric mean ratio with 90% CI in CYP2D6 EMsubjects Comparison Parameter Estimate 90% CI Severe RI vs C_(max) 0.878(0.462 to 1.669) Healthy AUC_(last) 0.994 (0.608 to 1.627) AUC 0.986(0.609 to 1.597) t_(1/2z) 0.776 (0.671 to 0.898) CL/F 1.014 (0.626 to1.643) Vz/F 0.787 (0.485 to 1.275) Note: The analysis model is log(PKparameter) = Population and conducted for EM subjects (7 severe RI and 7Healthy).

Eliglustat geometric mean C_(max) and AUC values were similar insubjects with severe RI and healthy matched subjects with CYP2D6 EMphenotype (0.878 and 0.986 fold, respectively). Coadministration of asingle weak CYP3A inhibitor (amlodipine) in CYP2D6 EM subjects withsevere RI (N=5, geometric mean [CV %] for C_(max) and AUC: 10.6 ng/mL[46.6] and 98.3 ng·h/mL [45.9], respectively) did not appear to resultin an increase in eliglustat exposures compared to severe RI EM subjectsreceiving eliglustat tartrate alone (N=2, geometric mean [CV %] forC_(max) and AUC: 15.2 ng/mL [12.9] and 104 ng·h/mL [30.3],respectively). Mean t_(1/2z) values were shorter in severe RI subjectsthan in healthy subjects (6.56 versus 8.50 hours) and t_(max) valueswere longer (4.0 versus 1.5 hours).

No definitive conclusion can be drawn for the effect of RI in CYP2D6 IMsas only one CYP2D6 IM with severe RI taking concomitant medications wasincluded. The substantially higher AUC_(last) values in this subjectcompared to CYP2D6 IM healthy subject (6.90-fold) or to either healthyCYP2D6 EMs (32.1-fold) or CYP2D6 EM with severe RI (35.2-fold) isattributed, at least in part, to the combined effect of 2 coadministeredCYP inhibitors, a CYP2D6 inhibitor (escitalopram) and a CYP3A inhibitor(amlodipine).

Safety Results:

A total of one mild TEAE was observed in 1 subject, and was consideredrelated to study drug by the investigator: fatigue in a healthy subject.No serious adverse events were reported, and there were no deaths orwithdrawals due to AEs. There were no treatment emergent PCSA that wereclinically relevant for the laboratory values or for vital signs andECGs.

Overall Conclusion:

The effects of mild and moderate hepatic impairment in a subject wereevaluated in a single dose phase 1 study described in Example 1. After asingle 84 mg dose, eliglustat C_(max) and AUC were 1.22- and 1.15-foldhigher in CYP2D6 EMs with mild hepatic impairment, and 2.81- and5.16-fold higher in CYP2D6 EMs with moderate hepatic impairment comparedto healthy CYP2D6 EMs.

Steady state exposures were predicted in CYP2D6 EMs with mild andmoderate hepatic impairment using the PBPK model. Doses of eliglustatthat would result in the mean steady state exposures within theefficacious and safe exposure ranges were proposed for CYP2D6 EMs withhepatic impairment when eliglustat is administered alone or with CYPinhibitors. Therefore, in extensive CYP2D6 metabolizers with mildhepatic impairment, no dosage adjustment (i.e., 84 mg BID) isrecommended when eliglustat is administered alone, and eliglustat dosageis reduced to 84 mg QD when eliglustat is taken with a weak CYP2D6inhibitor, or a strong, moderate, or weak CYP3A inhibitor. Eliglustat iscontraindicated in extensive CYP2D6 metabolizers with moderate hepaticimpairment and in extensive CYP2D6 metabolizers with mild hepaticimpairment when coadministered with a strong or moderate CYP2D6inhibitor since the mean steady state exposures were predicted muchhigher than the upper end of efficacious and safe exposure ranges.Eliglustat is contraindicated in patients with severe hepatic impairmentdue to a potential of substantially elevated plasma concentrations ofeliglustat. A contraindication for eliglustat use in CYP2D6 IMs or PMswith mild and moderate hepatic impairment is proposed since the steadystate exposures are unknown.

The effect of severe renal impairment was evaluated in a single dosephase 1 study described in Example 2. After a single 84 mg dose,eliglustat C_(max) and AUC were similar in CYP2D6 EMs with severe renalimpairment and healthy CYP2D6 EMs.

Considering the lack of effect of severe renal impairment after singledoses, repeated administration of eliglustat in CYP2D6 EMs is notexpected to have an impact on eliglustat exposure, since the timedependent effect due to mechanism-based inhibition of CYP2D6 is notexpected to be affected by renal impairment. Therefore, no doseadjustment is proposed for CYP2D6 EMs with mild, moderate and severe RI.

Limited or no data are available in CYP2D6 EMs, IMs or PMs withend-stage renal disease and in CYP2D6 IMs or PMs with mild, moderate, orsevere renal impairment; use of eliglustat in these patients should beavoided or not recommended.

1. A method of treating Gaucher disease comprising administering to apatient in need thereof an effective amount of eliglustat, or apharmaceutically acceptable salt thereof, wherein said patient is anextensive CYP2D6 metabolizer with mild hepatic impairment.
 2. The methodaccording to claim 1, wherein the effective amount is a twice daily doseof 84 mg of eliglustat, or a pharmaceutically acceptable salt thereof,measured in base form.
 3. The method according to claim 2 wherein theeliglustat or pharmaceutically acceptable salt thereof is eliglustathemitartrate.
 4. A method of treating Gaucher disease comprisingadministering to a patient in need thereof an adjusted effective amountof eliglustat, or a pharmaceutically acceptable salt thereof, whereinsaid patient is an extensive CYP2D6 metabolizer with mild hepaticimpairment and wherein said patient is concurrently taking a drug thatis a weak CYP2D6 inhibitor.
 5. The method according to claim 4 whereinthe adjusted effective amount is a once daily dose of 84 mg ofeliglustat or a pharmaceutically acceptable salt thereof, measured inbase form.
 6. The method according to claim 5, wherein the eliglustat orpharmaceutically acceptable salt thereof is eliglustat hemitartrate. 7.A method of treating Gaucher disease comprising administering to apatient in need thereof an adjusted effective amount of eliglustat, or apharmaceutically acceptable salt thereof, wherein said patient is anextensive CYP2D6 metabolizer with mild hepatic impairment and whereinsaid patient is concurrently taking a drug that is a weak CYP3Ainhibitor.
 8. The method according to claim 7, wherein the adjustedeffective amount is a once daily dose of 84 mg of eliglustat or apharmaceutically acceptable salt thereof, measured in base form.
 9. Themethod according to claim 8, wherein the eliglustat or pharmaceuticallyacceptable salt thereof is eliglustat hemitartrate. 10.-12. (canceled)13. A method of providing eliglustat, or a pharmaceutically acceptablesalt thereof, wherein the eliglustat, or pharmaceutically acceptablesalt thereof, is provided along with information indicating that it isuseful for treating patients with Gaucher disease, and in cases whereinsaid patient is an extensive CYP2D6 metabolizer with mild hepaticimpairment, no dose adjustment is required.
 14. An article ofmanufacture comprising a) a packaging material; b) eliglustat, or apharmaceutically acceptable salt thereof; and c) a label or packageinsert contained within the packaging material indicating thateliglustat, or a pharmaceutically acceptable salt thereof, iscontraindicated in CYP2D6 intermediate metabolizers (IMs) or poormetabolizers (PMs) with any degree of hepatic impairment and in CYP2D6extensive metabolizers (EMs) with moderate or severe hepatic impairment.15. A package comprising eliglustat, or a pharmaceutically acceptablesalt thereof, and a label, said label comprising a printed statementwhich informs a prospective user that eliglustat, or pharmaceuticallyacceptable salt thereof, is i) indicated for the treatment of Gaucherdisease type 1 and ii) is contraindicated in CYP2D6 intermediatemetabolizers (IMs) or poor metabolizers (PMs) with any degree of hepaticimpairment and in CYP2D6 extensive metabolizers (EMs) with moderate orsevere hepatic impairment.
 16. A method for treating Gaucher disease,comprising administering an adjusted effective amount of eliglustat, ora pharmaceutically acceptable salt thereof, to a patient in need thereofin combination with a weak CYP2D6 inhibitor, wherein said patient is aCYP2D6 extensive metabolizer and wherein said patient has mild hepaticimpairment.
 17. The method according to claim 16 wherein the adjustedeffect amount of eliglustat, or pharmaceutically acceptable saltthereof, is a dose of 84 mg of eliglustat, measured in base form, oncedaily.
 18. The method according to claim 17, wherein the eliglustat orpharmaceutically acceptable salt thereof is eliglustat hemitartrate. 19.A method for treating Gaucher disease, comprising administering anadjusted effective dose of eliglustat, or a pharmaceutically acceptablesalt thereof, to a patient in need thereof in combination with a weakCYP3A inhibitor, wherein said patient is a CYP2D6 extensive metabolizerand wherein said patient has mild hepatic impairment.
 20. The methodaccording to claim 19, wherein the adjusted effect amount of eliglustat,or pharmaceutically acceptable salt thereof, is a dose of 84 mg ofeliglustat, measured in base form, once daily.
 21. The method accordingto claim 20, wherein the eliglustat or pharmaceutically acceptable saltthereof is eliglustat hemitartrate.